Neuronal pentraxin II is highly upregulated in Parkinson’s disease and a novel component of Lewy bodies

Neuronal pentraxin II (NPTX2) is the most highly upregulated gene in the Parkinsonian substantia nigra based on our whole genome expression profiling results. We show here that it is a novel component of Lewy bodies and Lewy neurites in sporadic Parkinson’s disease (PD). NPTX2 is also known as the neuronal activity-regulated protein (Narp), which is secreted and involved in long-term neuronal plasticity. Narp further regulates AMPA receptors which have been found to mediate highly selective non-apoptotic cell death of dopaminergic neurons. NPTX2/Narp is found in close association with alpha-synuclein aggregates in both substantia nigra and cerebral cortex in PD but unlike alpha-synuclein gene expression, which is down-regulated in the Parkinsonian nigra, NPTX2 could represent a driver of the disease process. In view of its profound (>800%) upregulation and its established role in synaptic plasticity as well as dopaminergic nerve cell death, NPTX2 is a very interesting novel player which is likely to be involved in the pathway dysregulation which underlies PD

Temperament and parental child-rearing style: unique contributions to clinical anxiety disorders in childhood

Both temperament and parental child-rearing style are found to be associated with childhood anxiety disorders in population studies. This study investigates the contribution of not only temperament but also parental child-rearing to clinical childhood anxiety disorders. It also investigates whether the contribution of temperament is moderated by child-rearing style, as is suggested by some studies in the general population. Fifty children were included (25 with anxiety disorders and 25 non-clinical controls). Child-rearing and the child’s temperament were assessed by means of parental questionnaire (Child Rearing Practices Report (CRPR) (Block in The Child-Rearing Practices Report. Institute of Human Development. University of California, Berkely, 1965; The Child-Rearing Practices Report (CRPR): a set of Q items for the description of parental socialisation attitudes and values. Unpublished manuscript. Institute of Human Development. University of California, Berkely, 1981), EAS Temperament Survey for Children (Boer and Westenberg in J Pers Assess 62:537–551, 1994; Buss and Plomin in Temperament: early developing personality traits. Lawrence Erlbaum Associates, Inc, Hillsdale, 1984s). Analysis of variance showed that anxiety-disordered children scored significantly higher on the temperamental characteristics emotionality and shyness than non-clinical control children. Hierarchical logistic regression analyses showed that temperament (emotionality and shyness) and child-rearing style (more parental negative affect, and less encouraging independence of the child) both accounted for a unique proportion of the variance of anxiety disorders. Preliminary results suggest that child-rearing style did not moderate the association between children’s temperament and childhood anxiety disorders. The limited sample size might have been underpowered to assess this interaction

IGFBP3 Colocalizes with and Regulates Hypocretin (Orexin)

Background: The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression. Methodology/Principal Findings: We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and coexpressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decrease

Early phase of plasticity-related gene regulation and SRF dependent transcription in the hippocampus

Hippocampal organotypic cultures are a highly reliable in vitro model for studying neuroplasticity: in this paper, we analyze the early phase of the transcriptional response induced by a 20 \ub5M gabazine treatment (GabT), a GABA-Ar antagonist, by using Affymetrix oligonucleotide microarray, RT-PCR based time-course and chromatin-immuno-precipitation. The transcriptome profiling revealed that the pool of genes up-regulated by GabT, besides being strongly related to the regulation of growth and synaptic transmission, is also endowed with neuro-protective and pro-survival properties. By using RT-PCR, we quantified a time-course of the transient expression for 33 of the highest up-regulated genes, with an average sampling rate of 10 minutes and covering the time interval [10 3690] minutes. The cluster analysis of the time-course disclosed the existence of three different dynamical patterns, one of which proved, in a statistical analysis based on results from previous works, to be significantly related with SRF-dependent regulation (p-value<0.05). The chromatin immunoprecipitation (chip) assay confirmed the rich presence of working CArG boxes in the genes belonging to the latter dynamical pattern and therefore validated the statistical analysis. Furthermore, an in silico analysis of the promoters revealed the presence of additional conserved CArG boxes upstream of the genes Nr4a1 and Rgs2. The chip assay confirmed a significant SRF signal in the Nr4a1 CArG box but not in the Rgs2 CArG box

Narp deletion blocks extinction of morphine place preference conditioning

As drug abuse can be viewed as a maladaptive form of neuronal plasticity, attention has focused on defining the synaptic plasticity mechanisms that mediate the long-term effects of these drugs. As Narp is secreted at synaptic sites and binds to the extracellular surface of AMPA receptors, it has been implicated in mediating enduring forms of synaptic plasticity. Accordingly, to assess its potential role in the long-lasting behavioral effects of drugs of abuse, we have investigated the impact of Narp deletion on sustained behavioral responses elicited by repeated morphine administration. Narp knockout mice display normal locomotor sensitization and conditioned place preference, but are markedly resistant to extinction of place preference. Thus, these findings indicate that Narp plays a selective role in extinction, possibly by its effects on AMPA receptor trafficking